Targeting FTO suppresses hepatocellular carcinoma by inhibiting ERBB3 and TUBB4A expression

作者全名："Jiang, Lingli; Liang, Rui; Luo, Qing; Chen, Zhe; Song, Guanbin"

作者地址："[Jiang, Lingli; Liang, Rui; Luo, Qing; Song, Guanbin] Chongqing Univ, Coll Bioengn, Key Lab Biorheol Sci & Technol, Minist Educ, Chongqing 400044, Peoples R China; [Chen, Zhe] Chongqing Med Univ, Sch Basic Med Sci, Dept Radiol Med, Chongqing 400016, Peoples R China"

通信作者："Song, GB (通讯作者)，Chongqing Univ, Coll Bioengn, Key Lab Biorheol Sci & Technol, Minist Educ, Chongqing 400044, Peoples R China.; Chen, Z (通讯作者)，Chongqing Med Univ, Sch Basic Med Sci, Dept Radiol Med, Chongqing 400016, Peoples R China."

来源：BIOCHEMICAL PHARMACOLOGY

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001259692900001

JCR分区：Q1

影响因子：5.8

年份：2024

卷号：226

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Hepatocellular carcinoma (HCC); N6-methyladenosine (m6A); FTO; FB23-2; ERBB3; TUBB4A

摘要："Fat mass and obesity-associated protein (FTO) is an N6-methyladenosine (m6A) demethylase and plays critical oncogenic roles in multiple cancers. Here we show that FTO is an effective target in hepatocellular carcinoma (HCC). FTO is highly expressed in patients with HCC. Genetic depletion of Fto dramatically attenuated HCC progression in mice. Pharmacological inhibition of FTO by FB23/FB23-2 markedly suppressed the proliferation and migration of HCC cell lines in vitro and inhibited HCC tumorigenicity in xeno-transplanted mice. Mechanistically, FB23-2 suppressed the expression of Erb-b2 receptor tyrosine kinase 3 (ERBB3) and human tubulin beta class Iva (TUBB4A) by increasing the m6A level in these mRNA transcripts. The decrease in ERBB3 expression resulted in the inhibition of Akt-mTOR signaling, which subsequently impaired the proliferation and survival of HCC cells. Moreover, FB23-2 disturbed the stability of the tubulin cytoskeleton, whereas overexpression of TUBB4A rescued the migration of HCC cells. Collectively, our study demonstrates that FTO plays a critical role in HCC by maintaining the proliferation and migration of cells and highlights the potential of FTO inhibitors for targeting HCC."

基金机构：National Science Foundation of China [11832008]

基金资助正文：<BOLD>Funding</BOLD> This work was supported by grants from the National Science Foundation of China (11832008) .